In our recently completed randomized clinical trial, low dose buprenorphine (BUP) up to 6 mg daily has shown limited efficacy for opioid or cocaine abuse, but in a dose ranging study we found that 12- 16 mg sublingual BUP daily reduced both opioid and cocaine abuse. In a related study we have shown some efficacy for desipramine (DMI) in cocaine abusing methadone (METH) treated patients, particularly those with depression. The DMI response has been poorer in METH than in non-METH cocaine abusers, possibly because METH interferes with DMI metabolism. This metabolic interference in stronger in women than men, although treatment response in women, particularly at six month follow-up after stopping DMI, in better than in men. This in a critical issue, since work by Arndt in male veterans has suggested a worse follow-up outcome with DMI than with placebo. Thus, both sex and depression may be important prognostic variables. Based on these data, this competing renewal requests four years' support for a 24 week double blind, randomized clinical trial in 160 cocaine and opioid dependent patients. Four 40 patient cells are compared: 1. BUP (16 mg) + DMI (150 mg), 2. BUP + placebo, 3. METH (65 mg) + DMI, 4. METH + placebo. During the 24 weeks patients will remain on either METH or BUP (double dummy), but for DMI a 12 week counter-balanced, cross-over design will be used to increase statistical power and facilitate analyses by gender and depression status. We hypothesize that the combination of DMI + BUP will be more effective than either agent alone, and that depressives and women may respond best. This results from the generally better response to DMI in depressives and from the lack of interference with DMI metabolism by BUP compared to METH in women.